Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation

Prashant Donthamsetti, Eduardo F. Gallo, David C. Buck, Edward L. Stahl, Ying Zhu, J. Robert Lane, Laura M. Bohn, Kim Neve, Christoph Kellendonk, Jonathan A. Javitch

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The dopamine (DA) D2 receptor (D2R) is an important target for the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson’s disease. However, the development of improved therapeutic strategies has been hampered by our incomplete understanding of this receptor’s downstream signaling processes in vivo and how these relate to the desired and undesired effects of drugs. D2R is a G protein-coupled receptor (GPCR) that activates G protein-dependent as well as non-canonical arrestin-dependent signaling pathways. Whether these effector pathways act alone or in concert to facilitate specific D2R-dependent behaviors is unclear. Here, we report on the development of a D2R mutant that recruits arrestin but is devoid of G protein activity. When expressed virally in “indirect pathway” medium spiny neurons (iMSNs) in the ventral striatum of D2R knockout mice, this mutant restored basal locomotor activity and cocaine-induced locomotor activity in a manner indistinguishable from wild-type D2R, indicating that arrestin recruitment can drive locomotion in the absence of D2R-mediated G protein signaling. In contrast, incentive motivation was enhanced only by wild-type D2R, signifying a dissociation in the mechanisms that underlie distinct D2R-dependent behaviors, and opening the door to more targeted therapeutics.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Arrestin
Dopamine D2 Receptors
Locomotion
GTP-Binding Proteins
Motivation
G-Protein-Coupled Receptors
Cocaine
Knockout Mice
Parkinson Disease
Schizophrenia
Neurons
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Donthamsetti, P., Gallo, E. F., Buck, D. C., Stahl, E. L., Zhu, Y., Lane, J. R., ... Javitch, J. A. (Accepted/In press). Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0212-4

Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. / Donthamsetti, Prashant; Gallo, Eduardo F.; Buck, David C.; Stahl, Edward L.; Zhu, Ying; Lane, J. Robert; Bohn, Laura M.; Neve, Kim; Kellendonk, Christoph; Javitch, Jonathan A.

In: Molecular Psychiatry, 01.01.2018.

Research output: Contribution to journalArticle

Donthamsetti, P, Gallo, EF, Buck, DC, Stahl, EL, Zhu, Y, Lane, JR, Bohn, LM, Neve, K, Kellendonk, C & Javitch, JA 2018, 'Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation', Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0212-4
Donthamsetti, Prashant ; Gallo, Eduardo F. ; Buck, David C. ; Stahl, Edward L. ; Zhu, Ying ; Lane, J. Robert ; Bohn, Laura M. ; Neve, Kim ; Kellendonk, Christoph ; Javitch, Jonathan A. / Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. In: Molecular Psychiatry. 2018.
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